Preeclampsia (PE), gestational proteinuric hypertension, complicates 3-7% of all pregnancies, and is a multisystem maternal disorder. Yearly 8,500,000 cases are reported worldwide, of which 5,000 are in Sweden. It is today the most common cause of death for both children and mothers during pregnancy.
PE has been named the disease of theories [Roberts, 2001] and was described as early as 3000 years ago by the ancient Egyptians [Stevens, 1975]. PE is still one of the dominating obstetric complications that cause perinatal and maternal morbidity and mortality. Clinical manifestations, i.e. hypertension and proteinuria, appear from 20 weeks of gestation onwards, but the underlying mechanisms may begin as early as at the time of implantation. As the disease progresses, angiospasmus in the brain and brain oedema may cause severe epileptic seizures—eclampsia [Lipstein et al., 2003].
The etiology for PE is still unknown; however recent data suggest that the disease evolves in two stages:
Stage 1. During placentation, a defect invasion of the placental cells, trophoblasts, into the muscle layers of the spiral arteries has been shown [Brosens et al., 2002; Page, 1939]. A growing body of evidence suggests that oxidative stress (see below) further aggravates vascular function in the placenta [Roberts, 1999], which in turn [Shennan et al., 2001] gives rise to impaired blood perfusion [Hung et al., 2002]. Vasoconstriction and elevated resistance to blood flow follow as a consequence. Our array results show involvement of genes in both redox regulation and inflammation [Hansson et al., 2005].
Stage 2. Decreased placental perfusion, in combination with oxidative stress, causes general endothelial cell damage within the placenta. In later part of stage 2, the endothelial inflammation also damage the maternal vascular system, the kidneys in particular, is a typical histological finding in PE [Roberts et al., 1989; de Groot and Taylor, 1993; Granger et al., 2001; Strevens et al, 2003]. The link between stage one and two has up to date not been known.
Generally, preeclampsia occurs in women during their first pregnancy, and more commonly affects teenagers and women over 35 years of age. Women with underlying diseases that predispose them to hypertension are also among those at greater risk for the development of this condition. Preeclampsia is a leading cause of maternal mortality and morbidity. It is accounting for 12-18% of all pregnancy-related maternal deaths (around 70 maternal deaths per year in the United States and an estimated 50,000 maternal deaths per year worldwide). It is also associated with a high perinatal mortality and morbidity, due primarily to iatrogenic prematurity. Neurological manifestations are common in preeclampsia, and include headaches, visual aberrations to more severe manifestations such as seizures, stroke, and cortical blindness. Delivery of the fetus and removal of the placenta is the only curative treatment for preeclampsia—a fact that has lead to the generally accepted theory that placental pathology is central to development of preeclampsia. Despite intensive research efforts, the aetiology of preeclampsia remains largely unknown.
As mentioned above, it is believed that inadequate placentation, resulting in reduced placental perfusion, is an early step in the development of PE. Reduced perfusion associated with increased vascular resistance can be detected with Doppler ultrasound, and women with evidence of increased resistance in the uterine arteries early in their pregnancies (“notching”) have a higher risk of developing PE than women without this finding. As PE progresses, the maternal vascular bed is affected, and a general endothelial inflammation is seen. Poor placental perfusion appears to result in a cascade of pathological changes: decreased oxygen delivery, oxidative stress, formation of reactive oxygen species, endothelial damage, increased vascular permeability, and inflammation (see FIG. 1).
The symptoms of preeclampsia typically appear in the third trimester of pregnancy and are usually detected by routine monitoring of the woman's blood pressure and urine. However, these monitoring methods are ineffective for diagnosis of the syndrome at an early stage. Early diagnosis could reduce the risk to the subject or developing fetus and high risk patients could more specifically be monitored. Furthermore, effective treatment, that today still is lacking, would be ideal in combination with early detection.
Some methods of diagnosis have been described in the prior art but none of these have yet been successfully used in the clinic on a large scale. For example can be mentioned: U.S. Pat. No. 5,079,171 and U.S. Pat. No. 5,108,898, which disclose that preeclampsia, pregnancy-induced hypertension, and eclampsia can be diagnosed by identifying the presence of an endothelial cell marker, cellular fibronectin, in a sample of blood, plasma or serum of a pregnant woman, for example, by using a sandwich or competition immunoassay. The cellular fibronectin derives from endothelial cells that are ruptured or disturbed during the disease process. U.S. Pat. No. 5,238,819 discloses the diagnosis of preeclampsia using an assay to measure a mitogenic factor in blood. The mitogenic factor is a proteinaceous compound of about 160 kDa and is capable of stimulating fibroblast mitosis. Its presence is detected by detecting radiolabelled thymidine uptake by cells activated by the sera or plasma of a preeclamptic subject. This marker appears after damage to the maternal vascular bed already has occurred, hence late in the disease progression.
WO 05/093413 (Yale University and Brigham and Women's Hospital) discloses a method of diagnosing of severe preeclampsia in a pregnant woman, comprising measuring the level of free haemoglobin in a cerebrospinal fluid sample.
Currently, there are no known cures for preeclampsia. Preeclampsia can vary in severity from mild to life threatening. A mild form of preeclampsia can remain mild with bed rest and frequent monitoring. For moderate to severe cases, hospitalization is necessary and blood pressure medication and anticonvulsant medications to prevent seizures are prescribed. If the condition becomes life-threatening to the mother or the baby, the only cure is to terminate the pregnancy often resulting in a pre-term delivered baby.
Clearly, the lack of therapy for preeclampsia coupled with the age-old lack of ability to diagnose it until the the disease has progressed to a more severe form, prompts the need for novel approaches for diagnosing and treating preeclampsia, which is a significant public health problem.